Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain
the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in
Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles
and JavaScript.
In this issue (p 413), Jonathan Tilly and his colleagues report the isolation of oogonial stem cells from mouse and adult human ovaries, and show that the human cells can generate oocytes in vitro and within human ovarian xenografts in vivo. The cover depicts mouse oogonial stem cell–derived oocytes that have been fertilized in vitro to produce embryos. Image courtesy of Yvonne White, Dori Woods and Jonathan Tilly (Massachusetts General Hospital and Harvard Medical School).
Despite intense efforts to rid the world of poliovirus, it continues to persevere. Given the serious limitations of the existing vaccines, the feasibility of eradication must be reassessed.
When Robert J. Beall joined the Cystic Fibrosis Foundation in 1980, he launched a program aimed at absorbing the early financial risk involved in drug development as a way to entice for-profit companies to get involved in cystic fibrosis research. That strategy was vindicated with the approval in January of the first small-molecule drug that directly interacts with the mutated protein responsible for cystic fibrosis. Elie Dolgin spoke with Beall to learn more about his organization’s pioneering approach to venture philanthropy.
Brain scans that map differences in how brain regions communicate while people lie idle in the imaging machine could one day provide clues about afflictions ranging from Alzheimer's disease to attention disorders. Roxanne Khamsi finds out why these so-called 'resting state' scans have made researchers and drug companies sit up and take notice.
Given the current challenges in research and development, it's increasingly apparent that collaboration between large pharmaceutical companies, academic teams and biotechnology enterprises is essential for converting basic biomedical discoveries into lifesaving medicines. But these partnerships work best when a neutral third party helps foster them.
Kinase inhibitors are now standard treatment for patients with lung cancer whose tumors harbor specific mutant kinases. Four recent studies, including three in this issue (pages 375–384), have identified new fusion proteins involving another receptor tyrosine kinase that may potentially be responsive to existing targeted therapies.
The kinase AKT has been regarded as an obligate intermediate in the insulin signaling pathway that suppresses glucose production by inhibiting the transcription factor forkhead box O1 (FoxO1) after meals. A new study shows that, without AKT-FoxO1 signaling, insulin still contributes to postprandial responses, revealing an AKT-independent pathway for insulin action that might be exploited to treat metabolic disease (pages 388–395).
Researchers have isolated a rare population of germline stem cells from adult mouse and human ovaries that are capable of forming oocytes. The ability to harvest such cells from human ovaries could change the options available for fertility preservation and the treatment of infertility (pages 413–421).
Combination-based antiretroviral therapy has been very successful in preventing disease progression in HIV-infected individuals. However, a rational method for predicting the effect of a particular drug combination on clinical outcome is needed. A new study takes us closer to this goal by computationally predicting the inhibitory effects of combinations of three antiretroviral drugs (pages 446–451).
This review highlights the importance of immunometabolism to obesity and metabolic diseases such as diabetes. The authors describe recent advances in dissecting the cellular and signaling networks that link the immune and metabolic systems together, and how these insights could be translated to develop new therapeutic strategies to combat metabolic disease.
The authors report a new type of genetic alteration in lung adenocarcinoma. Fusions of KIF5B with RET kinase are found in 1–2% of lung cancer patients, segregate from other known alterations and can potentially be targeted using RET kinase inhibitors.
Through an integrated screening system, the authors catalog ALK and ROS1 fusions in lung cancer and identify a new class of fusions involving KIF5B and RET that may represent new therapeutic targets in adenocarcinoma.
Using high-coverage targeted next-generation sequencing, this report provides a catalog of genetic alterations in colorectal and lung cancers, identifying previously unknown alterations, such as JAK2 mutations and KIF5B-RET fusions, that may represent druggable targets.
Morphine loses its ability to fight pain after chronic use. Now, Howard Gutstein and his colleagues report that morphine induces release of PDGF, and blockade of PDGFR signaling can reestablish morphine analgesic efficacy in rats that have become tolerant.
The insulin signaling pathway regulating glucose homeostasis that has been well accepted is insulin-to-insulin receptor-to-IRS proteins-to-PI3K-to-Akt-to-Foxo1—a pathway that does not respond properly in states of insulin resistance, including type 2 diabetes. In a new study from Morris Birnbaum and colleagues, an alternative insulin signaling pathway has been uncovered, as mice with liver-specific deletion of Akt and Foxo1 still respond normally to nutritional cues and properly regulate glucose metabolism. Although the exact nature of this alternative pathway needs to be identified, the results should open many new avenues of exploration in the field of type 2 diabetes.
BMP7 has been previously shown to protect against renal fibrosis. Raghu Kalluri and his colleagues have now identified activin-like kinase 3 (Alk3) as the key co-receptor for BMP7 in the kidney and have identified an orally available, small-peptide agonist of Alk3 that reduces established fibrosis in five animal models of kidney injury.
In a new study, Yasuhiro Kobayashi and his colleagues show that noncanonical Wnt signaling regulates balanced osteoblast-induced osteoclastogenesis during normal physiology and that this pathway is perturbed in pathophysiological states, such as rheumatoid arthritis. These results explain further how osteoblasts cross-talk with preosteoclasts to ensure matched bone resorption with bone formation during skeletal homeostasis in the adult and also suggest a new target to treat arthritis.
In 2004, a team led by Jonathan Tilly reported that mice contained oogonial stem cells (OSCs), suggesting that females may be able to generate new oocytes in adulthood—a concept that was, and still is, quite controversial even though those findings have since been replicated by others. In a new report, Tilly and colleagues now perfect the purification of mouse OSCs and, using this technique, they show that similar cells exist in women of reproductive age. They also show that the mouse and human OSCs are able to give rise to oocytes in vivo (in the case of the human cells after xenotransplantation into NOD-SCID mice), while also showing that the mouse OSCs can give rise to embryos after in vitro fertilization.
CD8+ T cells primed in the absence of CD4+ T cell help fail to develop a robust memory cell response. Zloza et al. now report that these CD4-unhelped CD8+ T cells can be rescued by activating their cell surface receptor NKG2D, which restores CD8+ T cell expansion and cytolytic activity during a recall response and protection in a mouse model of influenza infection.
TGF-β signaling is commonly aberrantly activated in gliomas and other tumors and can exert a pro-oncogenic function. The authors identify a new mechanism for upregulation of TGF-β signaling in cancer. The deubiquitinase USP15 is shown to be able to bind the TGF-β receptor complex, counteract its degradation and potentiate its stimulation of downstream mediators. USP15 is amplified in human glioblastoma and could represent a therapeutic target, as its downregulation impairs the growth of glioblastoma cells in vivo.
The authors apply reverse engineering of transcriptional networks to identify the main functional drivers of the pro-leukemic transcriptional activity of TLX1 and TLX3, transcription factors usually altered in T-ALL. The network analysis uncovers RUNX1 as a key mediator of the effects of TLX factors and, consistently, mutations in RUNX1 are found in human T-ALL.
IgA antibodies directed against tissue transglutaminase 2 (TG2) are used as a serological marker of celiac disease. Ludvig M. Sollid and his colleagues provide an unbiased and thorough characterization of the mucosal antibody response directly from the effector compartment. They report that TG2-specific plasma cells are expanded in the duodenal mucosa of individuals with celiac disease. Antibodies cloned from these cells are of high affinity, show a restricted repertoire and minimal somatic hypermutation, and do not inhibit TG2 enzymatic activity.
Antiretroviral drug combinations for the treatment of HIV-1 infection have been determined on the basis of clinical trial outcomes, but without clear insight into why certain combinations are superior to others. Robert Siliciano and his colleagues present a quantitative basis for determining efficacious antiretroviral drug combinations.
Neuromuscular disease is often marked by insufficient neural activation of muscle activity, resulting in muscle weakness. Fady Malik and colleagues have developed an orally available small molecule that sensitizes muscles to neural activity by reducing the off rate of calcium binding to troponin C. They validate the therapeutic potential of this drug in vivo in a rat model of myasthenia gravis and show that treatment improves grip strength by 50%.
Targeting mesenchymal stem cells (MSCs), progenitors of osteoblasts, to bone has been a long-standing goal but has had limited success so far. Here, Min Guan and her colleagues deliver a peptidomimetic integrin ligand against integrin α4β1 conjugated to the bone-seeking agent bisphosphonate alendronate as a means of attracting infused and/or endogenous MSCs to the bone surface to stimulate bone formation. The approach was tested in both xenotransplantation and immunocompetent mice, as well as in mouse models of trabecular bone loss induced by aging and estrogen deficiency (ovariectomy).
There are currently no good ways to track human cells in vivo in a clinical setting using magnetic resonance imaging (MRI) based on superparamagnetic iron-oxide nanoparticles. Mya Thu and colleagues have introduced a simple magnetic cell labeling approach that combines three currently US Food and Drug Administration–approved drugs—ferumoxytol, heparin and protamine—to form self-assembling nanocomplexes of about 150 nm in size that effectively label cells for MRI. The approach was shown to effectively label three types of stem cells and two types of immune cells.